PXD011926 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Lztr1 loss leads to Noonan syndrome-like vascular defects by dysregulating vesicular trafficking |
Description | Mutations in LZTR1, an adaptor for cullin 3 (CUL3) ubiquitin ligase complex, are associated with glioma, hepatocarcinoma, paediatric cancers, Schwannomatosis, and Noonan syndrome (NS). NS is a poorly understood and complex disease. The variety of NS phenotypes makes it challenging to elucidate the molecular mechanisms by which mutations in LZTR1 drive human disease. Using an Lztr1 knockout model, we assessed the effect of Lztr1 loss on endothelial function. Moreover, the molecular alterations mediated by Lztr1 loss were evaluated by mass-spectrometry (MS)-based ubiquitome and proteome analysis. These analyses demonstrated that Lztr1 loss affects vesicular trafficking. We identified the ESCRT III member CHMP1B as a substrate for the LZTR1/CUL3 ubiquitin complex and could show that disease-related LZTR1 mutations abolish the interaction with CHMP1B. LZTR1-mediated ubiquitination of CHMP1B facilitates its interaction with IST1 that affects the dynamics of fusion and fission of endosomal vesicles. Dysregulation of vesicular trafficking triggered by Lztr1 loss leads to up-regulation of VEGF signaling due to endosomal accumulation and activation of VEGFR2. This novel molecular mechanism provides a fundamental explanation for the role of LZTR1 in endothelial function and justify the use of anti-VEGF therapies for the treatment of NS patients. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_05:13:26.275.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Impens Francis |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | ubiquitinylated lysine; monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue |
Instrument | Q Exactive HF; LTQ Orbitrap Elite |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2018-12-03 08:27:16 | ID requested | |
1 | 2020-10-13 22:59:52 | announced | |
⏵ 2 | 2024-10-22 05:13:27 | announced | 2024-10-22: Updated project metadata. |
Publication List
10.1161/circresaha.119.315730; |
Sewduth RN, Pandolfi S, Steklov M, Sheryazdanova A, Zhao P, Criem N, Baietti MF, Lechat B, Quarck R, Impens F, Sablina AA, Controls Cardiovascular Function by Regulating Vesicular Trafficking. Circ Res, 126(10):1379-1393(2020) [pubmed] |
Keyword List
curator keyword: Biomedical |
submitter keyword: HeLa cells, VEGF,Noonan syndrome, Lztr1, vesicular trafficking, ubiquitin, CHMP1B |
Contact List
Anna A Sablina |
contact affiliation | VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium Department of Oncology, KU Leuven, Herestraat 49, Leuven, Belgium |
contact email | anna.sablina@kuleuven.vib.be |
lab head | |
Impens Francis |
contact affiliation | VIB Proteomics Core Ghent University |
contact email | francis.impens@vib-ugent.be |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD011926
- Label: PRIDE project
- Name: Lztr1 loss leads to Noonan syndrome-like vascular defects by dysregulating vesicular trafficking